Dronedarone is a known drug for the treatment of arrhythmia and has the chemical name of N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5-yl]methanesulfonamide [see also formula (I) below]. There are some known processes for the preparation of dronedarone as follows:
In EP 0471609 the following scheme is disclosed for the preparation of dronedarone [Process A]

The above mentioned patent description discloses some new intermediary compounds, too.
In WO 02/48078 the following scheme is disclosed for the preparation of dronedarone [Process B]:

The novelty of the process is based on the adaptation of the Friedel-Crafts reaction in the first step. The process and the intermediary compounds used for the preparation of the benzoylchloride compound of the first step are also disclosed in this document. The further steps of the process are identical with the final steps of the synthetic route disclosed in EP 0471609 [Process A], but in the claims the whole synthetic route is claimed, up to dronedarone.
In WO 02/48132 (Sanofi) the following reaction route is disclosed [Process C]. This method is the so called superconvergent route. In the first step of it 5-amino-2-butyl-benzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran (in HCl salt form) is further reacted in the next step as follows:

In this process the order of reaction steps are altered, the reduction and the methansulfonylation steps are performed at the beginning of the procedure. Besides the reaction route for preparation of dronedarone, the starting material 2-butyl-5-methansulfonamido-benzofuran and its preparation is also claimed.
From among the mentioned procedures the first one [Process A] is the so called linear synthesis. In this way of procedure the different parts of the dronedarone are stepwise built up on the starting compound. This method is the least economical because the step by step building of the chemical groups is performed where more and more complicated and expensive molecules are applied which rises the costs of preparation. Furthermore, it comprises complicated and dangerous reaction step because aluminium chloride is used in the cleaving reaction of the methoxy group which makes the industrial feasibility more complicated.
In WO 02/48078 (Process B) a shorter synthetic route is disclosed which makes this process more economical, but its last reaction step remained the methansulfonylation reaction of the amino group. This reaction step (see the method described in example 6 of of WO 02/48078) is complicated and give a low yield, only 61.6%. Pure product can be obtained after purification using chromatographic column purification, which method is necessary because of the separation difficulties of the bis-methanesulfonylated product.
The process disclosed in WO 02/48132 (process C) is simpler and more economical taken into consideration the number of the reaction steps. Unfortunately, in the last reaction step rather impure dronedarone.HCl (hydrochloride) is formed which is the obvious consequence of the presence of dibutylamino group in the Friedel-Crafts reaction. According to Examples 3 and 4, the crude dronedarone hydrochloride is prepared with a yield of 90% which is further purified and finally the crude dronedarone base is produced with a yield of 86%. This base is reacted with hydrogen chloride gas dissolved in isopropanol which results in pure dronedarone hydrochloride salt. No yield is given for this reaction step. According to example 5 crude dronedarone hydrochloride salt is prepared with a yield of 90%, which is washed with water and reacted with hydrogen chloride gas dissolved in isopropanol, resulting dronedarone hydrochloride salt again. The quality of this product is not known. However, neither the components used in the Friedel-Crafts reaction nor the resulted products and by-products are soluble in water, the washing step with water cannot result any purification apart from the removal of inorganic salts.
There is another drawback of this process, namely, a dimesylated side-product is formed in the mesylation reaction of the 5-amino-2-butyl-benzofuran. The purification is carried out by crystallization which has a yield of 78.5%.
It is known from example 3 of EP 0 471 609 (Process A) that the methanesulfonylation reaction of amino group in preparation of dronedarone is performed in dichloromethane solvent in presence of triethylamine as acid binding agent and using methanesulfonyl chloride as methanesulfonylating reagent. The reaction is performed at room temperature, probably, since the applied temperature is not given. The reaction time is 20 hours. The yield of crude dronedarone is 100% but pure dronedarone can be prepared from the crude material only with a yield of 61.6%. In another example the purification of crude dronedarone is made by hexane. The yield of this purification step is 56.5%. The purity of the obtained pure dronedarone is 96.1% (HPLC).
In example 35 of EP 0 471 609 (Process A) the methanesulfonylation reaction of 2-n-butyl-5-amino-benzofurane is disclosed. The solvent is carbon tetrachloride and trietylamine is applied as base and methanesulfonyl chloride is used as methanesulfonylating reagent in an amount of 3 equivalents. After 6 hours reaction time the 2-(bis-methanesulfonamido)-2-n-butyl-benzofurane[3] is separated.
It is quite obvious from these two experiments that the selective mono-methanesulfonylation of the amino group is difficult and, according to example 3 mentioned before, beside the unreacted amino compound bis-methanesulfonylated compound (2) is also present. This is the reason of the moderate yield of the purification of crude dronedarone and of the relatively low purity level of 96.1% (HPLC) (which disables the direct use of the obtained material for pharmaceutical purpose).
It is an object of present invention to provide a novel process for the preparation of dronedarone of formula (I), starting with known and commercially available materials, applying simple and environmentally compatible reagents and solvents to afford high overall yields and good purity of the product.